US5648485A - β, β-dihydroxy meso-substituted chlorins, isobacteriochlorins, and bacteriochlorins - Google Patents

β, β-dihydroxy meso-substituted chlorins, isobacteriochlorins, and bacteriochlorins Download PDF

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US5648485A
US5648485A US08/329,577 US32957794A US5648485A US 5648485 A US5648485 A US 5648485A US 32957794 A US32957794 A US 32957794A US 5648485 A US5648485 A US 5648485A
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compound
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substituted
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David Dolphin
Christian Bruckner
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University of British Columbia
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Assigned to BRITISH COLUMBIA, UNIVERSITY OF reassignment BRITISH COLUMBIA, UNIVERSITY OF ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRUCKNER, CHRISTIAN, DOLPHIN, DAVID
Priority to PL95319907A priority patent/PL182239B1/pl
Priority to CZ19971155A priority patent/CZ294496B6/cs
Priority to PCT/CA1995/000602 priority patent/WO1996013504A1/fr
Priority to CA002199399A priority patent/CA2199399C/fr
Priority to AU36951/95A priority patent/AU704971B2/en
Priority to AT95944791T priority patent/ATE250064T1/de
Priority to DK95944791T priority patent/DK0804439T3/da
Priority to EP95944791A priority patent/EP0804439B1/fr
Priority to DE69531795T priority patent/DE69531795T2/de
Priority to HU9701702A priority patent/HU221102B1/hu
Priority to NZ294203A priority patent/NZ294203A/xx
Priority to KR1019970702735A priority patent/KR970707129A/ko
Priority to JP51420596A priority patent/JP3228296B2/ja
Priority to ES95944791T priority patent/ES2208701T3/es
Priority to CN95195859A priority patent/CN1043143C/zh
Priority to PT95944791T priority patent/PT804439E/pt
Priority to TW084113113A priority patent/TW301648B/zh
Priority to FI971734A priority patent/FI971734A0/fi
Priority to MXPA/A/1997/003013A priority patent/MXPA97003013A/xx
Priority to NO971952A priority patent/NO308411B1/no
Priority to US08/853,115 priority patent/US5831088A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0485—Porphyrins, texaphyrins wherein the nitrogen atoms forming the central ring system complex the radioactive metal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to certain dihydroxy chlorin, bacteriochlorin or isobacteriochlorin compounds and their preparation.
  • the invention relates to the dihydroxylation of ⁇ , ⁇ '-unsubstituted tetrapyrrolic macrocycles that have been substituted in some or all four meso-positions with an alkyl group or an aromatic ring.
  • Many of these compounds are useful photosensitizers in the field of photodynamic therapy ("PDT”) for mediating the destruction of unwanted cells or tissues or other undesirable materials by irradiation.
  • PDT photodynamic therapy
  • various tetrapyrrolic macrocycles such as purpurins, chlorins, bacteriochlorins, phthalocyanines and benzochlorins have shown the ability both to localize at a tumor site and to absorb light to form an activated state in response to the light. These macrocycles then exhibit a cytotoxic effect on the cells or other tissues in which they are localized when irradiated at the appropriate wavelength.
  • ⁇ -substituted porphyrins can be treated with osmium tetroxide (OsO 4 ) to oxidize one or more double bonds, thus forming an osmate ester at the ⁇ , ⁇ '-position, which can then be reduced with any one of a variety of reducing agents to form the corresponding vicinal-diol.
  • OsO 4 osmium tetroxide
  • the corresponding diol was obtained by oxidizing octaethylporphyrin with OsO 4 in the presence of pyridine.
  • Vicinal-dihydroxychlorins have been obtained from ⁇ , ⁇ '-alkyl substituted porphyrins by oxidation with osmium tetroxide in pyridine, and it has been confirmed that the product undergoes a pinacol rearrangement on treatment with sulfuric acid. See Bonnett et al., "The Oxidation of Porphyrins with Hydrogen Peroxide in Sulphuric Acid", Proc. Chem. Soc., 371-72 (1964), and Chang et al., "Differentiation of Bacteriochlorin and Isobacteriochlorin Formation by Metallation. High Yield Synthesis of Porphyrindiones via OsO 4 Oxidation", J. Chem.
  • ⁇ , ⁇ '-unsubstituted, meso-substituted porphyrin compounds can be ⁇ , ⁇ '-dihydroxylated via the addition of OsO 4 , followed by reduction to give the vic-diol, as shown below: ##STR5##
  • the resulting meso-substituted vic-diols are unexpectedly stable. Surprisingly, dehydration and rearrangement only takes place under relatively harsh conditions, such as treatment with refluxing benzene containing catalytic amounts of HClO 4 .
  • the high symmetry of the starting materials causes the formation of only one regio- and stereoisomer of the resulting chlorin.
  • the dihydroxylation of meso-tetraphenylporphyrin generates only one isomer of ⁇ , ⁇ '-dihydroxy-meso-tetraphenylbacteriochlorin.
  • subsequent ⁇ , ⁇ '-dihydroxylation of the ⁇ , ⁇ '-hydroxychlorin generates only two, easily separable diastereomers of the tetrahydroxybacteriochlorin product. This significant reduction of isomers provides a method for obtaining PDT agents in high yields, which is of great practical, economical and medicinal importance.
  • the meso-substituent can be widely derivatized, particularly when it is an aryl ring, such as a phenyl group.
  • a aryl ring such as a phenyl group.
  • A is a ring having the structure: ##STR8##
  • D is a ring having the structure: ##STR9##
  • R 1 through R 6 are independently a hydrogen atom, a lower alkyl group, a lower alkyl carboxylic acid or acid ester group, keto, hydroxy, nitro, amino or a group that, taken together with another ring, ring substituent or meso-substituent, forms a fused 5- or 6-membered ring; and
  • S 1 through S 4 are H, substituted or unsubstituted alkyl groups, or substituted or unsubstituted aromatic rings, which may be the same or different, with the proviso that at least one of S 1 through S 4 is not H.
  • a method for making a compound having formula (I) comprises the steps of:
  • the first comprises the steps of:
  • the second method of making a demetallated compound of formula (II) comprises the steps of:
  • FIG. 1 shows the UV-Vis spectrum of 2,3-vic-dihydroxy-tetraphenylchlorin (solid line) and the UV-Vis spectrum of [2,3-vic-dihydroxy-tetraphenylchlorinato] zinc (II) (broken line).
  • FIG. 2 shows the UV-Vis spectrum of 2,3-vic-dihydroxy-tetraphenylbacteriochlorin.
  • FIG. 3 shows the UV-Vis spectrum of 2,3,12,13-tetrahydroxy-tetraphenylbacteriochlorin-E-isomer (solid line) and the UV-Vis spectrum of 2,3,12,13-tetrahydroxy-tetraphenylbacteriochlorin-Z-isomer (broken line).
  • FIG. 4 shows the UV-Vis spectrum of [7,8-vic-dihydroxy-tetraphenylisobacteriochlorinato]zinc(II).
  • FIG. 5 shows the UV-Vis spectrum of 2,3,7,8-tetrahydroxy-tetraphenylisobacteriochlorin-E-isomer (solid line) and [2,3,7,8-tetrahydroxy-tetraphenylisobacteriochlorinato]zinc(II)-E-isomer (broken line).
  • the ⁇ , ⁇ '-dihydroxy meso-substituted chlorin, bacteriochlorin or isobacteriochlorin compounds of the invention have formula (I) or formula (II), as described and shown above.
  • M in formula (I) can be any metal species that is capable of forming the complex of formula (I), but is preferably selected from the group consisting of Ni(II), Cu(II), Zn, Sn, Ge, Si, Ga and Al.
  • An important characteristic of the metal selected is that it should be possible to introduce the metal into the porphyrin structure and then also possible to remove it from the chlorin resulting from the process of the invention.
  • A can be any ring having the structure: ##STR12##
  • D can be any ring having the structure: ##STR13## It should be understood that all corresponding resonance forms of the above structures are also intended to be covered by the terms "A" and "D".
  • at least one of the rings A and D is identical to the rings B and C. Even more preferably, both rings A and D are identical to the other rings B and C and, with them, form a porphyrin core structure having four such rings, each ring being connected by a bridging carbon atom that is referred to as the meso-position.
  • R 1 through R 6 can be any one of a large number of ring substituents, so long as they do not interfere with the osmylation and reduction steps outlined above.
  • R 1 through R 6 are independently a hydrogen atom; a lower alkyl group, such as methyl, ethyl, n-propyl, isopropyl, t-butyl and n-pentyl; a lower alkyl carboxylic acid, such as formyl, carboxymethyl, carboxyethyl, carboxy-n-butyl, carboxy-sec-butyl, carboxy-n-hexyl; a carboxylic acid ester group, such as --CH 2 CH 2 COOCH 3 , --CH 2 CH 2 COOCH 2 CH 3 , --CH 2 CH(CH 3 )COOCH 2 CH 3 , --CH 2 CH 2 CH 2 COOCH 2 CH 2 CH 3 , --CH 2 CH(CH 3 ) 2 COOCH 2 CH 3 ; keto; hydroxy;
  • R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 can be taken together with another ring, ring substituent or meso-substituent to form a fused 5- or 6-membered ring.
  • the fused 5- or 6-membered ring so formed may be any saturated or unsaturated, carbocyclic or heterocyclic 5- or 6-membered ring that does not interfere with the osmylation and reduction reaction steps of the invention.
  • rings examples include cyclopentane, furan, thiophene, pyrrole, isopyrrole, 3-isopyrrole pyrazole, 2-isoimidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2-dithiole, 1,3-dithiole, 1,2,3-oxathiole, isoxazole, oxazole, thiazole, isothiazole, 1,2,3-oxadiathiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-dioxazole, 1,2,4-dioxazole, 1,2,5-oxathiazole, 1,3-oxathiole, benzene, cyclohexane, 1,2-pyran, 1,4-pyran, 1,2-pyrone, 1,4-pyrone, 1,2-dioxin, 1,3-dioxin (dihydride
  • R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 form a fused, 5- to 6-membered ring
  • the ring is a 6-membered ring.
  • R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 form a ring, it is a 6-membered carbocyclic ring, i.e., a benzene ring.
  • R 1 through R 6 are independently hydrogen, methyl, ethyl, or lower alkyl esters, most preferably being hydrogen, methyl or ethyl.
  • S 1 through S 4 are the same or different and can be H, any one of a large number of substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, and aromatic rings.
  • S 1 through S 4 is an alkyl group, they preferably have from about 1 to about 18 carbon atoms, more preferably about 1 to 12 carbon atoms and, even more preferably, about 1-6 carbon atoms.
  • Examples of typical alkyl groups are methyl, ethyl, isopropyl, sec-butyl, tert-butyl, n-pentyl and n-octyl.
  • one or more of S 1 through S 4 is an alkyl group
  • it may be unsubstituted or substituted with any group that does not interfere with the osmylation or reduction reactions.
  • one or more of S 1 through S 4 is an alkyl group may be substituted by a halogen atom, such as fluorine, chlorine or bromine; a hydroxy group, such as in pentoses and hexoses; thiol; or a carbonyl group, such as when the alkyl group is an aldehyde, ketone, carboxylic acid (e.g., a fatty acid) or ester or amide; a primary, secondary, tertiary, or quaternary amino group; nitrile; a phosphate group; a sulfonate group; and the like.
  • a halogen atom such as fluorine, chlorine or bromine
  • a hydroxy group such as in pentoses and hexoses
  • thiol or
  • S 1 through S 4 When one or more of S 1 through S 4 is a cycloalkyl group, it preferably contains from about 3 to about 7 carbon atoms. Examples of typical cycloalkyl groups include cyclopropyl, cyclohexyl, and cycloheteroalkyl, such as glucopyranose or fructofuranose sugars.
  • S 1 through S 4 When one or more of S 1 through S 4 is a cycloalkyl group, it may be unsubstituted or substituted with any group that does not interfere with the osmylation or reduction reactions.
  • S 1 through S 4 when one or more of S 1 through S 4 is a cycloalkyl group, they may be substituted by any of the same substituents described above for the case when one or more of S 1 through S 4 is an alkyl group.
  • S 1 through S 4 When one or more of S 1 through S 4 is an aryl group, it preferably contains from about 5 to about 12 carbon atoms, optionally containing one or more heteroatoms, and optionally including rings that are fused to the existing conjugated porphyrin ring structure.
  • aromatic rings examples include furan, thiophene, pyrrole, isopyrrole, 3-isopyrrole, pyrazole, 2-isoimidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2-dithiole, 1,3-dithiole, 1,2,3-oxathiole, isoxazole, oxazole, thiazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-dioxazole, 1,2,4-dioxazole, 1,3,2-dioxazole, 1,3,4-dioxazole, 1,2,5-oxathiazole, 1,3-oxathiole, benzene, 1,2-pyran, 1,4-pyrazo
  • S 1 through S 4 are selected from the group consisting of phenyl, naphthyl, pyridinyl, and lower N-alkyl pyridinium salts. Even more preferably, S 1 through S 4 are identical.
  • At least one of S 1 through S 4 has the structure: ##STR14## wherein X, Y, Z, X', Y' and Z' can be any one of a large number of substituents and are generally used to "fine tune" the biological activity, the biodistribution, the absorption and clearance characteristics, and the physical properties of the desired product.
  • substituents in such a manner that the compound of formula (I) or (II) is an amphiphilic molecule.
  • amphiphilic is meant the molecule becomes more asymmetric, such as
  • the invention also includes ⁇ , ⁇ '-dihydroxy meso-substituted chlorin, bacteriochlorin or isobacteriochlorin compounds having substantially or exactly identical aryl substituents. Further, any aryl substituent chosen should also have no adverse effect on the ability of the compound to undergo the step "a.” and step “b.” reactions used to prepare the compounds of the invention.
  • X, X', Y, Y' and Z are independently (1) hydrogen; (2) halogen, such as fluoro, chloro, iodo and bromo; (3) lower alkyl, such as methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl and the like groups; (4) lower alkoxy, such as methoxy, ethoxy, isopropoxy, n-butoxy, t-pentoxy and the like; (5) hydroxy; (6) carboxylic acid or acid salt, such as --CH 2 COOH, --CH 2 COO-Na + , --CH 2 CH(Br)COOH, --CH 2 CH(CH 3 )COOH, --CH(Cl)-CH 2 -CH(CH 3 )-COOH, --CH 2 -CH 2 -C(CH 3 ) 2 -COOH, --CH 2 -CH 2 -C(CH 3 ) 2 -COOH, --CH
  • biologically active group can be any group that selectively promotes the accumulation, elimination, binding rate, or tightness of binding in a particular biological environment.
  • one category of biologically active groups is the substituents derived from sugars, specifically, (1) aldoses such as glyceraldehyde, erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, and talose; (2) ketoses such as hydroxyacetone, erythrulose, rebulose, xylulose, psicose, fructose, sorbose, and tagatose; (3) pyranoses such as glucopyranose; (4) furanoses such as fructofuranose; (5) O-acyl derivatives such as penta-O-acetyl- ⁇ -glucose; (6) O-acyl derivatives
  • Amino acid derivatives are also useful biologically active substituents, such as those derived from valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, alanine, arginine, aspartic acid, cystine, cysteine, glutamic acid, glycine, histidine, proline, serine, tyrosine, asparagine and glutamine.
  • peptides particularly those known to have affinity for specific receptors, for example, oxytocin, vasopressin, bradykinin, LHRH, thrombin and the like.
  • nucleosides for example, ribonucleosides such as adenosine, guanosine, cytidine, and uridine; and 2'-deoxyribonucleosides, such as 2'-deoxyadenosine, 2'-deoxyguanosine, 2'-deoxycytidine, and 2'-deoxythymidine.
  • ribonucleosides such as adenosine, guanosine, cytidine, and uridine
  • 2'-deoxyribonucleosides such as 2'-deoxyadenosine, 2'-deoxyguanosine, 2'-deoxycytidine, and 2'-deoxythymidine.
  • ligand specific for a receptor refers to a moiety that binds a receptor at cell surfaces, and thus contains contours and charge patterns that are complementary to those of the biological receptor.
  • the ligand is not the receptor itself, but a substance complementary to it. It is well understood that a wide variety of cell types have specific receptors designed to bind hormones, growth factors, or neurotransmitters. However, while these embodiments of ligands specific for receptors are known and understood, the phrase "ligand specific for a receptor”, as used herein, refers to any substance, natural or synthetic, that binds specifically to a receptor.
  • ligands examples include: (1) the steroid hormones, such as progesterone, estrogens, androgens, and the adrenal cortical hormones; (2) growth factors, such as epidermal growth factor, nerve growth factor, fibroblast growth factor, and the like; (3) other protein hormones, such as human growth hormone, parathyroid hormone, and the like; and (4) neurotransmitters, such as acetylcholine, serotonin, dopamine, and the like. Any analog of these substances that also succeeds in binding to a biological receptor is also included.
  • the steroid hormones such as progesterone, estrogens, androgens
  • growth factors such as epidermal growth factor, nerve growth factor, fibroblast growth factor, and the like
  • other protein hormones such as human growth hormone, parathyroid hormone, and the like
  • neurotransmitters such as acetylcholine, serotonin, dopamine, and the like. Any analog of these substances that also succeeds in binding to a biological receptor is also included.
  • substituents tending to increase the amphiphilic nature of the compound of formula (I) include: (1) long chain alcohols, for example, --C 12 H 24 -OH where --C 12 H 24 is hydrophobic; (2) fatty acids and their salts, such as the sodium salt of the long-chain fatty acid oleic acid; (3) phosphoglycerides, such as phosphatidic acid, phosphatidyl ethanolamine, phosphatidyl choline, phosphatidyl serine, phosphatidyl inositol, phosphatidyl glycerol, phosphatidyl 3'-O-alanyl glycerol, cardiolipin, or phosphatidal choline; (4) sphingolipids, such as sphingomyelin; and (5) glycolipids, such as glycosyldiacylglycerols, cerebrosides, sulfate esters of cerebrosides or gangliosides
  • X, X', Y, Y' and Z are independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid or acid salt, carboxylic acid ester, sulfonic acid or acid salt, sulfonic acid ester, substituted or unsubstituted amino, cyano, nitro, or a biologically active group, and Z' is hydrogen or lower alkyl.
  • X, Y, X' and Y' are each hydrogen, and Z is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid, carboxylic acid ester, sulfonic acid ester (especially aromatic sulfonic acid ester), nitro, amino (especially lower alkyl amino), cyano, and a biologically active group.
  • X, Y, Z, X' and Y' are selected from the group consisting of hydrogen, methyl, ethyl, t-butyl, methoxy, hydroxy, OR where R is an alkyl group or a fatty acid group having from 6 to 18 carbon atoms, fluoro, chloro, iodo, bromo, --C(O)-OCH 3 , cyano, nitro, or a ligand specific for a biological receptor.
  • X, X', Y and Y' and Z is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid or acid salt, carboxylic acid ester, sulfonic acid ester, sulfonic acid or acid salt, nitro, amino, cyano, and a biologically active group.
  • at least one of X, Y, Z, X' and Y' is a biologically active group or a substituent that increases the amphiphilic nature of the molecule.
  • Step "a.” of the process of making the compounds of the invention comprises osmylating a meso-substituted metalloporphyrin of formula (III), or the corresponding demetallated porphyrinogenic of formula (IV), to form an osmate ester at the ⁇ , ⁇ '-position.
  • the starting meso-substituted metalloporphyrin (III) or porphyrin (IV) for this reaction can be prepared by any one of a number of standard procedures. Examples include such techniques as:
  • the compound of formula (III) used as the starting material for step "a.” is prepared by using the Lindsey et al. method for synthesizing porphyrins (see above).
  • a general procedure for carrying out such a reaction is set forth below: Typically, an equimolar mixture of pyrrole and an appropriately substituted benzaldehyde are reacted under a nitrogen atmosphere with acid catalysis. Oxidation of the formed porphyrinogen with air or treatment with DDQ as an oxidant gives the porphyrin, which is then typically purified by column chromatography.
  • step "a.” The osmylation reaction of step "a.” is be carried out by treating the starting material with OsO 4 in the presence of a base, typically pyridine, thus forming an osmate ester at the ⁇ , ⁇ '-position, as shown below: ##STR20##
  • the amount of the OsO 4 is generally stoichiometric, and typically varies from about 1.0 to about 1.5 moles OsO 4 per mole of starting material.
  • the base usually used with the OsO 4 is generally one that is able to coordinate to the osmium(IV) in the osmate ester and that, thereby, stabilizes this intermediate and speeds up the formation of the osmate ester. See, for example, Schroder, "Osmium Tetroxide Cis Hydroxylation of Unsaturated Substrates", Chem. Rev., 80:187-218 (1980).
  • Preferred bases include pyridine, imidazole, isoquinoline, tert-alkyl amines such as trimethylamine, methylsulfonamide and the like.
  • the amount of base used can vary widely, so long as a sufficient amount is present saturate the coordination sphere of the osmium(VI) in the osmate ester. Preferably, however, the amount of base used falls within the range of about 2 to about 20 equivalents. Some bases, such as pyridine, can also be used as solvents or co-solvents for the osmylation reaction.
  • OsO 4 can be added to a reaction mixture neat, it is best used dissolved in a suitably non-reactive solvent.
  • a solvent depends on the substituent pattern on the porphyrin starting material, which affects its solubility.
  • solvents include aromatic solvents, such as pyridine, toluene and benzene; chlorinated solvents, such as CHCl 3 and dichloromethane; water; ethers, such as diethyl ether, tetrahydrofuran, diethylene glycol and glycol dimethyl ether (ethylene glycol dimethyl ether); ketones such as acetone and methyl ethyl ketone; acetonitrile; DME, DMF and DMSO; alcohols such as ethanol, methanol and butanol; and mixtures thereof.
  • aromatic solvents such as pyridine, toluene and benzene
  • chlorinated solvents such as CHCl 3 and dichloromethane
  • water ethers, such as diethyl ether, tetrahydrofuran, diethylene glycol and glycol dimethyl ether (ethylene glycol dimethyl ether); ketones such as acetone and methyl ethyl ketone; acetonitrile
  • the preferred solvent is water.
  • particularly useful solvent systems include combinations of chlorinated solvents, such as CHCl 3 and dichloromethane, mixed with about 2-25 volume % pyridine.
  • the temperature of the reaction mixture during step "a.” can vary widely but, typically, is maintained at room temperature or cooled somewhat to a temperature in the range of about -10° C. to room temperature. Preferably, the reaction is carried out at about room temperature.
  • the time required for the osmylation reaction of step "a.” will depend to a large extent on the temperature used and the relative reactivities of the starting materials. Particularly when the meso-substituents are aryl or a bulky alkyl group, such as tert-butyl, the reaction time tends to be relatively slow due to steric hindrance of the ⁇ -positions against the attack of the incoming osmium (VIII) species of OsO 4 (complexed with a base such as pyridine).
  • the tetra-substituted systems at least where one or more of S 1 through S 4 are particularly bulky such as a tert-butyl group, a cycloalkyl group, or a substituted phenyl ring, may require a significantly longer time to go to completion. Therefore, the reaction time can vary greatly, for example, from about 1 hour to about 7 days.
  • the osmylation reaction can be carried out at pressures both above and below atmospheric pressure. Preferably, however, the reaction is carried out at a pressure about equal to atmospheric pressure.
  • the reaction can be carried out in the presence of a mixture of gases approximating air but, when particularly reactive reactants are involved, the gaseous mixture may be enriched with an inert gas, such as nitrogen gas, argon, and the like.
  • the osmylation step of the invention can be carried out under conditions of normal, ambient lighting. However, because the substrates and products of the osmylation are often good photosensitizers, the exclusion of light is generally preferred to minimize side reactions.
  • the progress of the reaction sometimes involves a color change of the reaction mixture, for example, from purple to green. If desired, this color change can be used to monitor the approximate degree of completion of the reaction.
  • Other known techniques such as various types of chromatography, especially TLC and HPLC, can also be used to follow the progress of the reaction by the disappearance of the starting material.
  • a reaction mixture results, from which the diol product is separated and purified by any conventional means, typically chromatographically.
  • the osmylation reaction mixture is used directly in the reduction step "b.” without the intervening isolation or purification of the intermediate(s) present in the reaction mixture being necessary.
  • the reduction of the osmylation reaction mixture to form the diol of formula (I) can be accomplished by many of the usual reducing agents.
  • useful reducing agents include gaseous H 2 S, HSO 3 - , BH 4 - , AlH 4 - , B 2 H 6 , H 2 with a Ni- or Pd- catalyst, Zn/H+ and the like.
  • particularly convenient reductants include H 2 S and HSO 3 - , of which H 2 S is more preferred.
  • reducing agents are used in combination with a suitably non-reactive organic or inorganic non-solvent, such as methanol, ethanol and the like, to aid in solubilizing the polar dihydroxylated product, especially when the product is an anionic or cationic species.
  • a co-solvent sometimes also facilitates the isolation and purification of the product.
  • a particularly preferred combination of reducing agent and non-solvent for step "b.” is H 2 S with methanol.
  • reducing agents that are particularly useful for direct addition to the reaction mixture at the end of the osmylation step "a.”, without the intervening isolation or purification of specific compounds in the osmylation reaction mixture, include: (1) treatment with H 2 S and methanol; and (2) vigorous stirring of the organic phase with a solution of HSO 3 - in H 2 O. In such cases, reduction may proceed at a satisfactory rate, as commonly occurs with the first method, or the reaction may occur dependably but at rate that may be significantly slower, as sometimes occurs with the second method. Thus, the rate of the reaction is often influenced by the type and combination of reducing agent, with or without the presence of a non-solvent to precipitate out the unused reducing agent.
  • the temperature of the reaction mixture during the reduction step "b.” can vary widely depending upon the reducing agent being used. For example, when gaseous H 2 S is being used as the reducing agent, the temperature is typically allowed to remain at about room temperature. When other reducing agents, however, the temperature can range from about 1° to about 100° C.
  • the time required for the reduction reaction of step “b.” will depend to a large extent on the temperature used and the relative reactivities of the starting materials but, preferably, is about room temperature.
  • the reduction reaction of step “b.” can be carried out in the presence of gases at a pressure both above and below atmospheric pressure. Most frequently, however, the reaction is carried out at a pressure about equal to atmospheric pressure.
  • a ⁇ , ⁇ '-dihydroxy meso-substituted chlorin, bacteriochlorin or isobacteriochlorin compound of formula (I) or formula (II) can be isolated by any conventional method, such as by drowning out in a non-solvent, precipitating out, extraction with any immiscible liquid, evaporation of a solvent, or some combination of these or other conventional methods.
  • the ⁇ , ⁇ '-dihydroxy compound of formula (I) or formula (II) may then be purified by any one or a combination of known purification techniques, such as recrystallization, various forms of column chromatography, trituration with a non-solvent or a partial solvent, countercurrent extraction techniques, and the like.
  • a known amount of 5,10,15,20-meso-tetraphenylporphyrin is suspended in a solvent mixture of about 40:1 CHCl 3 :pyridine and mixed with 1.3 equivalents OsO 4 .
  • the reaction mixture is stirred in the dark for about 4 days.
  • the reaction is quenched by purging with gaseous H 2 S for a few minutes.
  • the precipitated black OsS is filtered off.
  • the filtrate is evaporated to dryness, chromatographed, for example, on silica/CH 2 Cl 2 -0.5% methanol, and further purified by recrystallization.
  • demetallation can take place at one of several stages during the process of the invention.
  • One can either (1) start with the demetallated meso-substituted porphyrinogenic compound having the formula (IV) shown below: ##STR21## or (2) osmylate the meso-substituted metalloporphyrin and remove the metal M from the compounds making up the reaction mixture after the osmylating step "a" and prior to the reducing step "b"; or (3) demetallate the ⁇ , ⁇ '-dihydroxy meso-substituted compound of formula (I) after the reducing step "b” to form a compound of formula (II).
  • the presence of the metal M is not generally required to carry out either the osmylation step "a" or the reduction step "b".
  • having a metal ion present increases the solubility of the starting material of the reaction, thus enabling a higher concentration of reactants and a shorter reaction time. Therefore, it is believed to be advantageous to have the metal present, particularly during the osmylation step "a" of the process of the invention.
  • other substituents on the meso-substituted compound may also have a significant effect on the solubility of the compound and thus also influence the concentration and reaction time.
  • the reaction conditions are usually the same or very similar.
  • Suitable demetallating reagents used for this purpose include any acid that is capable of demetallating, but which does not induce the formation of oxo-porphyrins.
  • the demetallating conditions should be selected to be compatible with the particular substituents present on the compound being demetallated.
  • the demetallating agent is selected from the group consisting of CH 3 COOH, CF 3 COOH, H 2 S, 1,3-propanedithiol, dilute hydrochloric acid in a suitable solvent such as water or chloroform, and mixtures thereof.
  • suitable mixtures of demetallating agents include: (1) dilute trifluoroacetic, (2) H 2 S, and (3) a two-phase system formed by chloroform and dilute (5%) aqueous hydrochloric acid.
  • solvents examples include water; alcohols, such as ethanol, methanol, iso-propanol and the like; haloalkanes such as methylene chloride and the like; nitrogen-containing solvents such as DMF, tetrahydrofuran and the like; relatively unreactive aromatic compounds such as benzene, toluene and the like; and ethers such as diethyl ether, diethylene glycol, and glycol dimethyl ether.
  • alcohols such as ethanol, methanol, iso-propanol and the like
  • haloalkanes such as methylene chloride and the like
  • nitrogen-containing solvents such as DMF, tetrahydrofuran and the like
  • relatively unreactive aromatic compounds such as benzene, toluene and the like
  • ethers such as diethyl ether, diethylene glycol, and glycol dimethyl ether.
  • the temperature of the reaction mixture during the demetallating process can vary widely but, typically, is maintained in the range of about 0° to 120° C.
  • refluxing acetic acid can be used as a demetallating agent in some circumstances, which would provide a temperature of about 118° C.
  • the demetallating reaction is most preferably carried out at about room temperature or below.
  • the time required for demetallation varies widely, depending on the temperature used and the relative reactivities of the starting materials, particularly the demetallating agents and the metal to be removed from the porphyrin. For example, when a two-phase system of 5% aqueous hydrochloric acid and chloroform is used to demetallate a zinc porphyrin, the reaction typically takes place in minutes. If, on the other hand, rearrangement is desirable, the metallated compound can be subjected to stronger acid conditions, such as dry hydrochloric gas in chloroform, to accomplish the rearrangement, remove the metal, or both.
  • the reaction can be carried out above or below atmospheric pressure. Preferably, the reaction is carried out at a pressure about equal to atmospheric pressure.
  • Straightforward procedures can be used to isolate the demetallated product, such as neutralization of the reaction mixture, extraction with any immiscible liquid, eluting on a silica gel column or other types of chromatography, drowning out in a non-solvent, precipitating out or otherwise crystallizing, evaporation of solvent, or some combination of these or other conventional methods.
  • Preferred methods of isolating the desired demetallated compound include chromatography and/or crystallization. If further purification of the demetallated product is desired, it may be subjected to additional purification procedures, such as recrystallization, eluting on a silica gel chromatography column, and combinations of these methods.
  • the ⁇ , ⁇ '-dihydroxy compounds resulting from step "a.” and step “b.” are vicinal diols.
  • the introduction of the vic-diol gives the molecule an amphiphilic character, a property believed to be important in the biodistribution of site-specific photochemotherapeutics.
  • the compounds of the invention are surprisingly stable toward dehydration and concomitant reconstitution of the porphyrin chromophore.
  • dilute HCl in CHCl 3 under reflux conditions can be successfully used to demetallate a chlorin of formula (I) where M is Zn, but without provoking undesirable rearrangement reactions.
  • a catalytic amount HClO 4 must also be added.
  • the ⁇ , ⁇ '-dihydroxy meso-substituted chlorin, bacteriochlorin and isobacteriochlorin compounds of the invention can also be subjected to reaction steps "a" and "b" a second time to add a second pair of hydroxy groups.
  • the relative position of the second pair of hydroxy groups depends on many factors, such as the presence of a metal, the selection of the metal when one is present, the relative bulk and electronic characteristics of the meso-substituents, and the presence and characteristics of additional ⁇ , ⁇ '-substituents.
  • the role of the metal M in directing a second pair of hydroxy substituents to preferred positions.
  • a demetallated diol chlorin of formula (II) is osmylated and reduced in accordance with the process of the invention, the second pair of hydroxy groups goes to the ⁇ , ⁇ '-positions on the opposite ring.
  • a metallated compound of formula (I) is used, e.g., one where M is zinc, the second pair of hydroxy groups is added to the ⁇ , ⁇ '-positions of an adjacent ring.
  • the ⁇ , ⁇ '-dihydroxy meso-substituted chlorin, bacteriochlorin or isobacteriochlorin compounds of the invention can also be dehydrated under acid catalysis to form the corresponding 2-oxy-(meso-tetraphenyl)porphyrins, if desired, thus forming the beginning of yet another synthetic pathway to this known class of compounds. While a few of these compounds are accessible via other methods, e.g. Catalano et al., "Efficient Synthesis of 2-Oxy-5,10,15,20-tetraphenylporphyrins from a Nitroporphyrin by a Novel Multistep Cine-substitution Sequence", J. Chem. Soc., Chem. Comm., 1537-38 (1984), many other compounds can be prepared via the dihydroxylation method of the invention. Specific examples of such compounds are shown below and include:
  • the ⁇ , ⁇ '-dihydroxy meso-substituted chlorin, bacteriochlorin and isobacteriochlorin compounds of the invention are useful as photosensitizers used in photodynamic therapy (PDT) and as synthetic intermediates for making related photosensitizers.
  • these photosensitizers are useful in sensitizing neoplastic cells or other abnormal tissues to destruction by irradiation with visible light.
  • the energy of photoactivation is believed to be transferred to endogenous oxygen, thus converting it to singlet oxygen. This singlet oxygen is thought by some to be responsible for the observed cytotoxic effect. Alternatively, there may be direct electron transfer from the photoactivated molecule.
  • Typical indications known in the art include diagnosis and destruction of tumor tissue in solid tumors, such as those of bronchial, cervical, esophageal or colon cancer; dissolution of plaques in blood vessels (see, e.g., U.S. Pat. No. 4,512,762, which is hereby incorporated by reference); treatment of topical conditions such as acne, athlete's foot, warts, papilloma and psoriasis; and treatment of biological products, such as blood for transfusion to eliminate infectious agents.
  • the metallated pigment compounds of the invention have diagnostic use in nuclear medicine.
  • M is Mn(III) or Gd(III)
  • the compounds may be useful in magnetic resonance imaging.
  • the photosensitizers made from the compounds of the invention can be formulated into pharmaceutical compositions for administration to the subject or applied to an in vitro target using techniques generally known in the art.
  • a summary of such pharmaceutical compositions may be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.
  • the compounds of the invention can be used singly or as components of mixtures.
  • the compound of the invention labeled or unlabeled, is administered systemically, such as by injection.
  • Injection may be intravenous, subcutaneous, intramuscular, or even intraperitoneal.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol and the like. Of course, these compositions may also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
  • Systemic administration can be implemented through implantation of a slow release or sustained release system, by suppository, or, if properly formulated, orally.
  • Formulations for these modes of administration are well known in the art, and a summary of such methods may be found, for example, in Remington's Pharmaceutical Sciences (supra).
  • the compound can be administered topically using standard topical compositions, such as lotions, suspensions, or pastes.
  • the quantity of the photosensitizer compound to be administered depends upon the choice of active ingredient, the condition to be treated, the mode of administration, the individual subject, and the judgment of the practitioner. Depending on the specificity of the preparation, smaller or larger doses may be needed. For compositions that are highly specific to target tissues, such as those with a highly specific monoclonal immunoglobulin preparation or a specific receptor ligand, dosages in the range of 0.05-1 mg/kg are suggested. For compositions that are less specific to the target tissue, larger doses, up to 1-10 mg/kg may be needed. The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon.
  • the compounds made from the intermediate compounds of the invention can be used in the treatment of materials in vitro to destroy harmful viruses or other infectious agents.
  • blood plasma or blood that is to be used for transfusion or banked for future transfusion can be treated with the compounds of the invention and irradiated to effect sterilization.
  • biological products such as Factor VIII, which are prepared from biological fluids, can be irradiated in the presence of the compounds of the invention to destroy contaminants.
  • the compounds of the invention can be "fine tuned” to produce a desired set of biological effects when administered to a subject in need of photodynamic therapy.
  • the solubility, biodistribution, and/or amphiphilicities of the compounds of the invention the corresponding isopropylidene ketal may be formed.
  • the invention provides methods for synthesizing such derivative compounds in an efficient manner with relatively few by-products or isomeric impurities.
  • the desired ⁇ , ⁇ '-dihydroxychlorin was recrystallized in CHCl 3 /methanol, m.p. >350° C.
  • the UV-vis spectrum of this ⁇ , ⁇ '-dihydroxychlorin was typical for chlorins and is shown in FIG. 1.
  • UV-Vis (CH 2 Cl 2 -0.1% MeOH): ⁇ [nm] (log ⁇ ) 408 (5.27) , 518 (4.19), 544 (4.19), 592 (3.85), 644 (4.38);
  • the preparation of the zinc metallated compound analogous to the compound of Example 1 above is based on the procedure of Example 1, except for being adapted to the higher solubility of the metallated starting compound, 5,10,15,20-meso-tetraphenylporphyrinato-zinc(I).
  • 520 mg (7.37 ⁇ 10 -4 mol) of the starting compound was dissolved in 20 ml of freshly distilled, ethanol-stabilized CHCl 3 , and treated with 5.0 ml freshly distilled pyridine and 225 mg (8.84 ⁇ 10 -4 mol, 1.2 equivalents) OsO 4 .
  • the reaction flask was stoppered and stirred at ambient temperature in the dark for 14 hours.
  • the reaction was quenched by purging with gaseous H 2 S for five minutes. Following the addition of 3 ml methanol, the precipitated black OsS was filtered off through a pad of diatomaceous earth (commercially available under the trade name Celite). The filtrate was evaporated to dryness, and the resulting residue was charged onto a silica gel column (100 g, 280-400 mesh) and initially eluted with dichloromethane to remove the unreacted starting material (55 mg, 111). A mixture of 0.5% methanol in dichloromethane was used to elute the desired ⁇ , ⁇ '-dihydroxy metallochlorin product (380 mg, 5.34 ⁇ 10 -4 mol, 72% yield).
  • the desired ⁇ , ⁇ '-dihydroxy metallochlorin was recrystallized in CHCl 3 /methanol, m.p. >350° C.
  • the UV-vis spectrum of the ⁇ , ⁇ '-dihydroxy metallochlorin was typical for metallochlorins and is shown in FIG. 1.
  • UV-Vis (CH 2 Cl 2 -0.1% MeOH): ⁇ [nm] (log ⁇ ) 418 (5.41), 614 (4.71);
  • R F 0.12 (silica gel, CH 2 Cl 2 /10.0% MeOH/2.0% pyridine);
  • UV-Vis(CH 2 Cl 2 ): ⁇ max 408 (sh), 424 (Soret), 526, 570, 598, 629 nm;
  • UV-Vis (CH 2 Cl 2 -0.5% MeOH): ⁇ [nm] (log ⁇ ) 378 (4.96), 524 (4.49), 724 (4.71);
  • Example 5 Preparation of the Two Isomeric Tetrahydroxytetraphenylbacteriochlorins, 2R,3S,12R, 13S-Tetrahydroxy-5,10,15,20-tetra phenylbacteriochlorin and 2R,3S,12S,12R-Tetrahydroxy-5,10,15,20-tetraphenylbacteriochlorin ##STR31##
  • UV-Vis (CH 2 Cl 2 -0.5% MeOH): ⁇ [nm] (log ⁇ ) 376 (5.42), 528 (5.08, 708 (4.89);
  • UV-Vis (CH 2 Cl 2 -0.5% MeOH): ⁇ [nm] (log ⁇ ) 376 (5.42), 528 (5.08), 708 (4.89);
  • the zinc chlorin Zn-2 was used as a starting compound. Under the dehydration conditions (refluxing CHCl 3 with a drop of concentrated HClO 4 ), the product was demetallated, yielding Cpd. 3. Less acid-labile complexes of Cpd. 2, like Ni-2 or Cu-2, were dehydrated under these conditions without concomitant demetallation. Under less harsh conditions (CHCl 3 containing a drop of concentrated HCl at room temperature), Zn-2 was demetallated without dehydration.
  • Zn-3 (2-oxy-5,10,15,20-tetraphenyl-porphyrinato) zinc(II)
  • Cpd. 3 was metallated with Zn(II)-acetate in pyridine/CHCl 3 to form Zn-3.

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US08/329,577 US5648485A (en) 1994-10-26 1994-10-26 β, β-dihydroxy meso-substituted chlorins, isobacteriochlorins, and bacteriochlorins
KR1019970702735A KR970707129A (ko) 1994-10-26 1995-10-25 β,β´-디하이드록시 메조-치환된 클로린, 이소 박테리오클로린, 박테리오클로린, 및 β,β´-비치환된 테트라피롤 매크로사이클로부터의 그 제조 방법(β,β´-DIHYDROXY MESO-SUBSTITUTED CHLORINS, ISOBACTERIOCHLORINS, BACTERIOCHLORINS, AND METHODS FOR MAKING THE SAME FROM β,β´-UNSUBSTITUTED TETRAPYRROLIC MACROCYCLES)
ES95944791T ES2208701T3 (es) 1994-10-26 1995-10-25 Clorinas, isobacterioclorinas, bacterioclorinas beta, beta'-dihidroximeso-sustituidas, y sus procedimientos de fabricacion a partir de macrociclos tetrapirrolicos beta, beta' no sustituidas.
PCT/CA1995/000602 WO1996013504A1 (fr) 1994-10-26 1995-10-25 CHLORINES, ISOBACTERIOCHLORINES, BACTERIOCHLORINES β,β'-DIHYDROXY MESO-SUBSTITUEES, ET LEURS PROCEDES DE FABRICATION A PARTIR DE MACROCYCLES TETRAPYRROLIQUES β,β' NON SUBSTITUES
CA002199399A CA2199399C (fr) 1994-10-26 1995-10-25 Chlorines, isobacteriochlorines, bacteriochlorines .beta.,.beta.'-dihydroxy mesosubstituees, et leurs procedes de fabrication a partir de macrocycles tetrapyrroliques .beta.,.beta.' non substitues
AU36951/95A AU704971B2 (en) 1994-10-26 1995-10-25 Beta, beta'-dihydroxy meso-substituted chlorins, isobacteriochlorins, bacteriochlorins, and methods for making the same from beta, beta'-unsubstituted tetrapyrrolic macrocycles
AT95944791T ATE250064T1 (de) 1994-10-26 1995-10-25 Beta, beta'-dihydroxy meso-substituierte chlorine,isobacteriochlorine und bacteriochlorine und verfahren zu ihrer herstellung aus beta, beta'- unsubstutuierten tetrapyrolischen macrocyclen
DK95944791T DK0804439T3 (da) 1994-10-26 1995-10-25 Beta, beta'-dihydroxy-mesosubstituerede chloriner, -isobacteriochloriner, -bacteriochloriner og fremgangsmåder til fremstilling af samme ud fra beta, beta'-usubstituerede tetrapyrroliske, makrocykliske forbindelser
EP95944791A EP0804439B1 (fr) 1994-10-26 1995-10-25 Chlorines, isobacteriochlorines, bacteriochlorines beta,beta'-dihydroxy meso-substituees, et leurs procedes de fabrication a partir de macrocycles tetrapyrroliques beta,beta' non substitues
DE69531795T DE69531795T2 (de) 1994-10-26 1995-10-25 Beta, beta'-dihydroxy meso-substituierte chlorine, isobacteriochlorine und bacteriochlorine und verfahren zu ihrer herstellung aus beta, beta'-unsubstutuierten tetrapyrolischen macrocyclen
HU9701702A HU221102B1 (en) 1994-10-26 1995-10-25 Beta,beta'-dihydroxy meso-substituted chlorins, bacteriochlorins, isobacteriochlorins, and process for preparing thereof
NZ294203A NZ294203A (en) 1994-10-26 1995-10-25 Chlorin derivatives such as isobacteriochlorin or bacteriochlorin and their preparation
PL95319907A PL182239B1 (pl) 1994-10-26 1995-10-25 ß , ß ‘-dihydroksy mezo-podstawione chloryny, bakteriochloryny lub izobakteriochlorynyi sposób ich wytwarzania. PL PL PL PL
JP51420596A JP3228296B2 (ja) 1994-10-26 1995-10-25 β，β’−ジヒドロキシメソ置換クロリン、イソバクテリオクロリン、バクテリオクロリン、およびβ，β’−非置換テトラピロールマクロサイクルからのそれらの製造方法
CZ19971155A CZ294496B6 (cs) 1994-10-26 1995-10-25 ß,ß´-Dihydroxy meso-substituované chloriny, izobakteriochloriny, bakteriochloriny a způsob jejich výroby z ß,ß´-nesubstituovaných tetrapyrrolových makrocyklů
CN95195859A CN1043143C (zh) 1994-10-26 1995-10-25 β,β-二羟基中位取代的二氢卟酚、异细菌二氢卟酚、细菌二氢卟酚,和从β,β-未取代的四吡咯大环制备所述化合物的方法
PT95944791T PT804439E (pt) 1994-10-26 1995-10-25 Clorinas isobacterioclorinas bacterioclorinas beta,beta'-di-hidroxi meso-substituidas e metodos para fabricar as mesmas a partir de macrociclos tetrapirrolicos beta-beta'-nao substituidos
TW084113113A TW301648B (fr) 1994-10-26 1995-12-08
FI971734A FI971734A0 (fi) 1994-10-26 1997-04-23 Beta, beta'-dihydroksi-menosubstituoidut kloriinit, isobakteriokloriinit, bakteriokloriinit ja menetelmä niiden valmistamiseksi beta, beta-substituoimattomista tetrapyrrolimakrosykleistä
MXPA/A/1997/003013A MXPA97003013A (en) 1994-10-26 1997-04-24 Beta chlorines, beta'-dihydroxy meso substitute, isobacterioclorines and methods to manufacture themselves from macrocicles tetrapirrolicosbeta, beta'-without substitute
NO971952A NO308411B1 (no) 1994-10-26 1997-04-25 <beta>,<beta>'-dihydroksy-meso-substituerte kloriner, isobakteriokloriner, bakteriokloriner og fremgangsmÕter for fremstilling av disse fra <beta>,<beta>'-usubstituerte tetrapyrrol- makrocykler
US08/853,115 US5831088A (en) 1994-10-26 1997-05-08 Methods to prepare ββ'-dihydroxy meso-substituted chlorins, isobacteriochlorins and bacteriochlorins
JP2001094418A JP2001294589A (ja) 1994-10-26 2001-03-28 β，β’−ジヒドロキシメソ置換クロリン、イソバクテリオクロリン、バクテリオクロリン、およびβ，β’−非置換テトラピロールマクロサイクルからのそれらの製造方法

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US5831088A (en) * 1994-10-26 1998-11-03 The University Of British Columbia Methods to prepare ββ'-dihydroxy meso-substituted chlorins, isobacteriochlorins and bacteriochlorins
US6376483B1 (en) 1999-05-27 2002-04-23 Miravant Pharmaceuticals, Inc. Bacteriochlorins and bacteriopurpurins useful as photoselective compounds for photodynamic therapy and a process for their production
US6444194B1 (en) 1997-02-14 2002-09-03 Miravant Pharmaceuticals, Inc. Indium photosensitizers for PDT
US6514926B1 (en) 1998-10-20 2003-02-04 The Procter & Gamble Company Laundry detergents comprising modified alkylbenzene sulfonates
US6583096B1 (en) 1998-10-20 2003-06-24 The Procter & Gamble Company Laundry detergents comprising modified alkylbenzene sulfonates
US6620929B1 (en) 1999-04-14 2003-09-16 University Of British Columbia 1,3-Dipolar cycloadditions to polypyrrolic macrocycles
US20030176663A1 (en) * 1998-05-11 2003-09-18 Eidgenossische Technische Hochscule Specific binding molecules for scintigraphy
US20040044198A1 (en) * 2002-07-02 2004-03-04 Pandey Ravindra K. Efficient synthesis of pyropheophorbide a and its derivatives
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US9096670B2 (en) 1996-05-24 2015-08-04 Philogen S.P.A. Antibodies of the ED-B domain of fibronectin, their construction and uses
US7273924B1 (en) 1996-05-24 2007-09-25 Philogen S.P.A. Antibodies to the ED-B domain of fibronectin, their construction and uses
US8703143B2 (en) 1996-05-24 2014-04-22 Philogen S.P.A. Antibodies of the ED-B domain of fibronectin, their construction and uses
US6444194B1 (en) 1997-02-14 2002-09-03 Miravant Pharmaceuticals, Inc. Indium photosensitizers for PDT
US8097254B2 (en) 1998-05-11 2012-01-17 Eidgenossische Technische Hochschule Zurich Specific binding molecules for scintigraphy, conjugates containing them and therapeutic method for treatment of angiogenesis
US20030176663A1 (en) * 1998-05-11 2003-09-18 Eidgenossische Technische Hochscule Specific binding molecules for scintigraphy
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US20040019201A1 (en) * 1999-04-14 2004-01-29 Macalpine Jill Kirsten 1,3-Dipolar cycloadditions to polypyrrolic macrocycles
US6825343B2 (en) 1999-04-14 2004-11-30 University Of British Columbia 1,3-dipolar cycloadditions to polypyrrolic macrocycles
US6620929B1 (en) 1999-04-14 2003-09-16 University Of British Columbia 1,3-Dipolar cycloadditions to polypyrrolic macrocycles
US7022843B1 (en) 1999-04-14 2006-04-04 The University Of British Columbia β,β′-dihydroxy meso-substituted chlorins, isobacteriochlorins, and bacteriochlorins
US6376483B1 (en) 1999-05-27 2002-04-23 Miravant Pharmaceuticals, Inc. Bacteriochlorins and bacteriopurpurins useful as photoselective compounds for photodynamic therapy and a process for their production
US20070053840A1 (en) * 1999-12-23 2007-03-08 Health Research, Inc. Multi DTPA conjugated tetrapyrollic compounds for phototherapeutic contrast agents
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US20050221434A1 (en) * 2000-09-07 2005-10-06 Andreas Menrad Receptor of the EDb-fibronectin domains
US20050090481A1 (en) * 2001-11-09 2005-04-28 Qlt Inc Compositions comprising a photosensitizer and a skin-penetration enhancer and their use in photodynamic treatment
USRE43274E1 (en) 2002-06-27 2012-03-27 Health Research, Inc. Fluorinated photosensitizers related to chlorins and bacteriochlorins for photodynamic therapy
US7820143B2 (en) 2002-06-27 2010-10-26 Health Research, Inc. Water soluble tetrapyrollic photosensitizers for photodynamic therapy
US20040044198A1 (en) * 2002-07-02 2004-03-04 Pandey Ravindra K. Efficient synthesis of pyropheophorbide a and its derivatives
US20060128683A1 (en) * 2003-01-16 2006-06-15 Nam-Tae Woo Novel use of porphyrin derivatives
US7019132B2 (en) 2003-01-16 2006-03-28 Kostarworld Co., Ltd. Porphyrin derivatives
US20050283861A1 (en) * 2003-06-26 2005-12-22 The J. C. Robinson Seed Co. Inbred corn line w23129
US6995260B2 (en) * 2004-05-20 2006-02-07 Brookhaven Science Associates, Llc Carboranylporphyrins and uses thereof
US20050260128A1 (en) * 2004-05-20 2005-11-24 Haitao Wu Carboranylporphyrins and uses thereof
US20090075295A1 (en) * 2005-11-30 2009-03-19 Lindsey Jonathan S Porphyrinic compounds for use in flow cytometry
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US20120244551A1 (en) * 2005-11-30 2012-09-27 Lindsey Jonathan S Porphyrinic compounds for use in flow cytometry
US8546088B2 (en) * 2005-11-30 2013-10-01 North Carolina State University Porphyrinic compounds for use in flow cytometry
US8980565B2 (en) * 2005-11-30 2015-03-17 North Carolina State University Porphyrinic compounds for use in flow cytometry
US9417245B2 (en) * 2005-11-30 2016-08-16 North Carolina State University Porphyrinic compounds for use in flow cytometry
WO2009038659A3 (fr) * 2007-09-14 2009-09-03 Health Research, Inc. Nanoparticules de silice organiquement modifiées avec des photosensibilisateurs incorporés par covalence pour l'administration de médicaments lors d'une thérapie photodynamique
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US20090167755A1 (en) * 2007-12-28 2009-07-02 Voth Eric J Method and system for generating surface models of geometric structures
US20110070154A1 (en) * 2008-08-13 2011-03-24 Hyde Roderick A Artificial cells
US20110070153A1 (en) * 2008-08-13 2011-03-24 Searete, Llc, A Limited Liability Corporation Of The State Of Delaware Artificial cells
US9691555B2 (en) 2014-07-01 2017-06-27 National Chung Hsing University Photosensitive porphyrin dyes for dye-sensitized solar cells

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US5831088A (en) 1998-11-03
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